Stem cell proliferation and cellular differentiation need to be tightly coordinated with the mitotic cell cycle. But how is this done at the mechanistic level? How do gene regulatory proteins, such as pluripotency factors and lineage-specific transcription factors, interact with the cell cycle machinery either to maintain stemness or to promote differentiation? And to what extent are the cell cycle proteins taking an active role in these developmental processes? This is by and large not known. The cell cycle has often been regarded as an independent self-perpetuating process, with the core cell cycle proteins controlling the progression from one cell cycle phase to the next in a relatively stereotypic manner. Growing evidence indicates, however, that close cross-talk between the cell cycle machinery and the regulatory transcription factor network may play a more profound role than previously anticipated.^[1]

In this issue of BioEssays, Muhr and Hagey^[2] present the hypothesis that the choice between stem cell maintenance and differentiation relies on direct interactions and reciprocal regulation between the cell cycle machinery and differentiation factors. It is further hypothesized that these pathways have co-evolved and are rooted in the diversification of cell cycle proteins and transcription factors during evolution. To back-up this hypothesis, the authors compared the repertoire of cell cycle factors, such as cyclins and cyclin-dependent kinases (CDKs), and differentiation factors in representative genomes of four phyla, from single eukaryotic yeast cells to humans. Not too surprisingly, the repertoire of these factors has increased dramatically during evolution. An intriguing observation is, however, that Trichoplax, which represents a basal branch of multicellular organisms with only six cell types, is equipped with a complete catalogue of cyclins, CDKs, and stem cell regulators. Thus the basic setup was there early in evolution, and the authors hypothesize that this may have enabled the diversification of stem cell identities and been a prerequisite for the evolvement of complex animal forms.

During early embryonic development cell cycles are generally very rapid, alternating between mitosis (M) and DNA synthesis (S) phases. In mammals, fast cell cycles are characteristic of pluripotency, while cell-lineage restriction is coupled to longer cell cycles, including gap phases, regulatory checkpoints, and cells may also enter quiescence.^[1] Weather the cell cycle length is a cause or consequence of pluripotency has not been entirely resolved. As pointed out,^[2] both quiescence and differentiation interfere with cell cycle progression and block proliferation, although the end points are opposite. It is generally accepted that quiescent stem cells are arrested after mitosis, but a recent study in Drosophila questions this dogma.^[3] Intriguingly, it was demonstrated that ≈75% of quiescent neural stem cells (qNSCs) are arrested before mitosis. Thus, new technologies enable challenges of old truths. Furthermore, transit amplifying cells are cell-lineage-restricted and committed to differentiation but do not exit the cell cycle until after several rounds. Muhr and Hagey hence reason that a deeper mechanistic insight is needed to be able to interpret such experimental results appropriately.

Inspired by the findings of their previous work,^[4] using single-cell RNA sequencing to study the sequential generation of layer-specific cortical neurons in mouse embryos, Muhr and Hagey now summarize^[2] the current knowledge of the mechanistic cross-talk between cell cycle proteins and differentiation factors, and how it affects the choice between stem cell maintenance versus lineage-restriction and neural differentiation. The lack of such mechanistic understanding in the development of other organ systems is also highlighted. Finally, a rationale for future investigation is presented, aiming to bring a more comprehensive insight into these fundamental processes.

干细胞增殖和细胞分化需要与有丝分裂细胞周期紧密协调。但是，这是如何在机械层面上完成的呢？基因调控蛋白，如多能性因子和谱系特异性转录因子，如何与细胞周期机制相互作用以维持干性或促进分化？细胞周期蛋白在这些发育过程中在多大程度上发挥了积极作用？这基本上是未知的。细胞周期通常被认为是一个独立的自我延续过程，核心细胞周期蛋白以相对刻板的方式控制着从一个细胞周期阶段到下一个阶段的进程。然而，越来越多的证据表明，^{[ 1 ]}

在本期BioEssays 中，Muhr 和 Hagey ^{[ 2 ]}提出干细胞维持和分化之间的选择依赖于细胞周期机制和分化因子之间的直接相互作用和相互调节的假设。进一步假设这些途径共同进化并且植根于进化过程中细胞周期蛋白和转录因子的多样化。为了支持这一假设，作者比较了细胞周期因子的库，如细胞周期蛋白和细胞周期蛋白依赖性激酶 (CDK)，以及四种门的代表性基因组中的分化因子，从单个真核酵母细胞到人类。毫不奇怪，这些因素在进化过程中急剧增加。然而，一个有趣的观察结果是Trichoplax代表多细胞生物的基础分支，只有六种细胞类型，配备了完整的细胞周期蛋白、CDK 和干细胞调节剂目录。因此，基本设置在进化的早期就存在，作者假设这可能使干细胞身份多样化成为可能，并且是复杂动物形态进化的先决条件。

在早期胚胎发育期间，细胞周期通常非常快，在有丝分裂 (M) 和 DNA 合成 (S) 阶段之间交替。在哺乳动物中，快速的细胞周期是多能性的特征，而细胞谱系限制与更长的细胞周期相关，包括间隙期、调节检查点，并且细胞也可能进入静止状态。^{[ 1 ]}天气细胞周期长度是多能性的原因或结果尚未完全解决。正如所指出的，^{[ 2 ]}静止和分化都会干扰细胞周期进程并阻止增殖，尽管终点是相反的。人们普遍认为，静止干细胞在有丝分裂后被阻滞，但最近的一项研究果蝇质疑这个教条。^{[ 3 ]}有趣的是，已证明约 75% 的静止神经干细胞 (qNSCs)在有丝分裂前被阻滞。因此，新技术使旧真理的挑战成为可能。此外，转运扩增细胞受细胞谱系限制并致力于分化，但直到几轮后才退出细胞周期。因此，Muhr 和 Hagey 认为需要更深入的机械洞察力才能正确解释此类实验结果。

受到他们之前工作发现的启发，^{[ 4 ]}使用单细胞 RNA 测序来研究小鼠胚胎中层特异性皮层神经元的顺序生成，Muhr 和 Hagey 现在总结^{[ 2 ]}机械串扰的当前知识细胞周期蛋白和分化因子之间的关系，以及它如何影响干细胞维持与谱系限制和神经分化之间的选择。还强调了在其他器官系统的发展中缺乏这种机制理解。最后，提出了未来调查的基本原理，旨在更全面地了解这些基本过程。